Clin Transplant Res.  2024 Dec;38(4):257-272. 10.4285/ctr.24.0059.

Advancing immunosuppression in liver transplantation: the role of regulatory T cells in immune modulation and graft tolerance

• Han JW
• Park SH

• KMID: 2563950
• DOI: http://doi.org/10.4285/ctr.24.0059

Abstract

Prolonged immunosuppressive therapy in liver transplantation (LT) is associated with significant adverse effects, such as nephrotoxicity, metabolic complications, and heightened risk of infection or malignancy. Regulatory T cells (Tregs) represent a promising target for inducing immune tolerance in LT, with the potential to reduce or eliminate the need for life-long immunosuppression. This review summarizes current knowledge on the roles of Tregs in LT, highlighting their mechanisms and the impact of various immunosuppressive agents on Treg stability and function. The liver’s distinct immunological microenvironment, characterized by tolerogenic antigen-presenting cells and high levels of interleukin (IL)-10 and transforming growth factor-β, positions this organ as an ideal setting for Treg-mediated tolerance. We discuss Treg dynamics in LT, their association with rejection risk, and their utility as biomarkers of transplant outcomes. Emerging strategies, including the use of low-dose calcineurin inhibitors with mammalian target of rapamycin inhibitors, adoptive Treg therapy, and low-dose IL-2, aim to enhance Treg function while providing sufficient immunosuppression. Thus, the future of LT involves precision medicine approaches that integrate Treg monitoring with tailored immunosuppressive protocols to optimize long-term outcomes for LT recipients.

Keyword

Liver transplantation; Regulatory T cell; Transplant rejection

Figure

• 

  Fig. 1 The role of Tregs in direct and indirect allorecognition pathways in graft rejection. This figure illustrates the role of Tregs in suppressing immune responses and preventing graft damage through direct and indirect allorecognition pathways. In the direct pathway, donor graft cells present alloantigens to recipient CD4+ T cells, while in the indirect pathway, recipient APCs present processed donor peptides. Both pathways activate CD8+ T cells and B cells, potentially leading to graft damage. Tregs inhibit T cell activation by depriving effector T cells of IL-2 (via CD25), suppressing dendritic cells through the CTLA-4/CD80 axis, and producing inhibitory cytokines (IL-10, IL-35, and TGF-β). They also modulate B cells via the PD-1/PD-L1 axis and generate adenosine (through CD39/CD73) to protect the graft. MHCII, major histocompatibility complex class II; TCR, T cell receptor; Treg, regulatory T cell; PD-1, programmed cell death protein 1; IL, interleukin; IFN-γ, interferon gamma; ADCC, antibody-dependent cell-mediated cytotoxicity; APC, antigen-presenting cell; TGF, transforming growth factor; DC, dendritic cell; CTLA-4, cytotoxic T-lymphocyte-associated protein 4.

• 

  Fig. 2 Effects of immunosuppressive regimens on Treg dynamics post-LT. This figure illustrates the impact of various immunosuppressive agents on Tregs following LT. Glucocorticoids initially increase Treg levels at low doses but decrease them at high doses. High doses of tacrolimus reduce Tregs, whereas mycophenolate mofetil has a neutral effect on Tregs. Basiliximab, administered on days 0 and 4, has a transient Treg depletion effect. Everolimus, which may be introduced around day 30, increases Treg levels. Early reduction of Tregs by day 7 is associated with a higher risk of graft rejection, as indicated by flow cytometry data for FOXP3+CD25+ Tregs. Treg, regulatory T cell; IV, intravenous; PO, oral; LT, liver transplantation.

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